In order to produce an effect, a drug must reach its target site in adequate concentration. This involves several processes embraced by the general term pharmacokinetics. In general, these processes are: (1) administration of the drug, (2) absorption from the site of administration into the bloodstream, (3) distribution to other parts of the body, including the target site, (4) metabolic alteration of the drug, and (5) excretion of the drug or its metabolites.

An important step in all these processes is the movement of drug molecules through cellular barriers (e.g., the intestinal wall, the walls of blood vessels, the barrier between the bloodstream and the brain, and the wall of the kidney tubule), which constitute the main restriction to the free dissemination of drug molecules throughout the body. To cross most of these barriers, the drug must be able to move through the lipid layer of the cell membrane. Drugs that are highly lipid-soluble do this readily; hence, they are rapidly absorbed from the intestine and quickly reach most tissues of the body, including the brain. They readily enter liver cells (one of the main sites of drug metabolism) and are consequently liable to be rapidly metabolized and inactivated. They can also cross the renal tubule easily and thus tend to be reabsorbed into the bloodstream rather than being excreted in the urine.

Non-lipid-soluble drugs (e.g., many neuromuscular blocking drugs) behave differently because they cannot easily enter cells. Therefore, they are not absorbed from the intestine, and they do not enter the brain. Because they may escape metabolic degradation in the liver, they are excreted unchanged in the urine. Certain of these drugs cross cell membranes, particularly in the liver and kidney, with the help of special transport systems, which can be important factors in determining the rate at which drugs are metabolized and excreted.

Drugs are given by two general methods: enteral and parenteral administration. Enteral administration involves the esophagus, stomach, and small and large intestines (i.e., the gastrointestinal tract). Methods of administration include oral, sublingual (dissolving the drug under the tongue), and rectal. Parenteral routes, which do not involve the gastrointestinal tract, include intravenous (injection into a vein), subcutaneous (injection under the skin), intramuscular (injection into a muscle), inhalation (infusion through the lungs), and percutaneous (absorption through intact skin).

After oral administration of a drug, absorption into the bloodstream occurs in the stomach and intestine, which usually takes about one to six hours. The rate of absorption depends on factors such as the presence of food in the intestine, the particle size of the drug preparation, and the acidity of intestinal contents. Intravenous administration of a drug can result in effects within a few seconds, making this a useful method for emergency treatment. Subcutaneous or intramuscular injection usually produces effects within a few minutes, depending largely on the local blood flow at the site of the injection. Inhalation of volatile or gaseous agents also produces effects in a matter of minutes and is mainly used for anesthetic agents.

The bloodstream carries drugs from the site of absorption to the target site and also to sites of metabolism or excretion, such as the liver, the kidneys, and in some cases the lungs. Many drugs are bound to plasma proteins, and in some cases more than 90 percent of the drug present in the plasma is bound in this way. This bound fraction is inert. Protein binding reduces the overall potency of a drug and provides a reservoir to maintain the level of the active drug in blood plasma. To pass from the bloodstream to the target site, drug molecules must cross the walls of blood capillaries. This occurs rapidly in most regions of the body. The capillary walls of the brain and spinal cord, however, are relatively impermeable, and in general only drugs that are highly lipid-soluble enter the brain in any appreciable concentration.

In order to alter or stop a drug’s biological activity and prepare it to be eliminated from the body, it must undergo one of many different kinds of chemical transformations. One particularly important site for these actions is the liver. Metabolic reactions in the liver are catalyzed by enzymes located on a system of intracellular membranes known as the endoplasmic reticulum. In most cases the resultant metabolites are less active than the parent drug; however, there are instances where the metabolite is as active as, or even more active than, the parent. In some cases the toxic effects of drugs are produced by metabolites rather than the parent drug.

Many different kinds of reactions are catalyzed by drug-metabolizing enzymes, including oxidation, reduction, the addition or removal of chemical groups, and the splitting of labile (chemically unstable) bonds. The product is often less lipid-soluble than the parent and is consequently excreted in the urine more rapidly. Many of the causes of variability in drug responses reflect variations in the activity of drug-metabolizing enzymes. Competition for the same drug-metabolizing enzyme is also the source of a number of drug interactions.

The main route of drug excretion is through the kidneys; however, volatile and gaseous agents are excreted by the lungs. Small quantities of drugs may pass into sweat, saliva, and breast milk, the latter being potentially important in breast-feeding mothers. Although some drugs are excreted mainly unchanged into the urine, most are metabolized first. The first stage in excretion involves passive filtration of plasma through structures in the kidneys called glomeruli, through which drug molecules pass freely. The drug thus reaches the renal tubule, where it may be actively or passively reabsorbed, or it may pass through into the urine. Many factors affect the rate of renal excretion of drugs, important ones being binding to plasma proteins (which impedes their passage through the glomerular filter) and urinary acidity (which can affect the rate of passive reabsorption of the drug by altering the state of its ionization).

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